S161: UBA1 NON-M41 VARIANTS ARE MORE AGGRESSIVE THAN UBA1 M41 VARIANTS IN THEIR HEMATOLOGICAL MANIFESTATIONS.
Authors: Maki Sakuma, Constance Baer, Manja Meggendorfer, Claudia Haferlach, Wolfgang Kern, Torsten Haferlach, Wencke Walter
Journal: HemaSphere (2023)

Background: The pathogenicity of UBA1 variants is currently under intense investigation in association to the newly described hematoinflammatory disease, VEXAS syndrome, and its frequent co-diagnosis with a preleukemic disease such as MDS. We have previously shown that patients carrying M41 variants were almost exclusively diagnosed with MDS but the patients harboring non-M41 variants experienced more diverse diagnoses. To further pursue this result, we sequenced the entire UBA1 coding region of 21,625 individuals with a suspected hematological malignancy. Aims: To compare UBA1 M41 and non-M41 variants in their occurrence in hematological neoplasms. Methods: 21,625 samples (12,524 males, 9,101 females) of patients with suspected hematological neoplasms, sent between 01/2022-12/2022 for diagnostic work-up, were analyzed by targeting sequencing including the entire coding region of UBA1. Bone marrow or peripheral blood samples were sequenced by standard protocols, and patients were diagnosed according to 2022 WHO classification. Putative somatic variants were defined as variants absent in gnomAD and VAF < 90% in males and an additional VAF < 40% and VAF > 60% filtering was imposed for females. Patients harboring putative somatic UBA1 variants were analyzed. Results: 42/21,625 (0.2%) patients harbored 27 different putative somatic UBA1 variants (3 M41, 1 splice site, 23 non-M41) with the known male bias (36 vs 6 cases). In 4/42 (9%) cases more than one UBA1 variant was detected. Among the six female patients harboring putative somatic UBA1 variants, no M41 variants or previously reported non-M41 variants were detected (Figure A). Two patients were diagnosed with MDS, one each with CMML, MPN, and mature B-cell neoplasm, and the other with reactive changes (Figure B). For the majority of female patients (67%) a normal karyotype was detected. In men, 21/36 (58%) patients harbored M41 variants and M41-altering splice variants, with one patient also harboring a novel variant. The patients were mainly diagnosed with MDS (1 MDS-IB1, 3 MDS-LB, 1 MDS-SF3B1) or were suspected of early MDS (n = 15), with the exception of one patient who was diagnosed with multiple myeloma (Figure B). However, cytomorphologically, an MDS component could not be excluded in the multiple myeloma patient who also displayed a normal karyotype. Overall, 90% of patients with M41 variants had a normal karyotype. 6/36 (17%) patients harbored previously reported non-M41 variants including three patients carrying additional novel variants and were diagnosed with MDS (MDS-IB1, MDS-RS), MN-pCT (n=2), AML (n=1), and CMML (n=1). Here, in 50% of the patients an aberrant karyotype was detected. Only novel putative somatic variants were detected in 9/36 patients (25%, Figure A). Among these patients, 4 received a diagnosis: MDS-RS, MPN, CMML, and mature B cell neoplasm. Others were suspected of MDS, CMML, MPN or had unclear changes in cytomorphology. 66% of patients with novel UBA1 variants had a normal karyotype. All patients diagnosed with AML or myeloid neoplasms with more than 10% blasts had additional mutations in known leukemia driver genes, including FLT3 and NRAS, EZH2 and SF3B1, and PHF6. Summary/Conclusion: The detection of M41 variants was restricted to MDS and MM cases, whereas the non-M41 variants were diagnosed with AML, CMML, and MPN, suggesting that patients harboring non-M41 variants may follow a more aggressive hematological course than the cytoplasmic-only loss of function variant M41.Keywords: VEXAS syndrome